Glucosamine is a valuable pharmacological agent in the treatment of a wide variety of ailments, for example the treatment of osteoarthritic conditions in animals and humans. Glucosamine is a natural substance found in high quantities in joint structures. More specifically, glucosamine 5-phosphate, is naturally occurring within the body and is a component in the biosynthesis of glycosaminoglycans, proteoglycans, hyaluronan and collagen.
The main function of glucosamine in joint structures is to produce cartilage components necessary for maintaining and repair joint tissue. Glucosamine stimulates the formation of joint structural components such as collagen, the protein of the fibrous substances that holds the joints together and helps to build-up the cartilage matrix. Collagen is the main component of the shock-absorbing cushion called articular cartilage. It is also a necessary nutrient in the production of synovial fluid. Some people may lose the ability with age to produce glucosamine, thereby inhibiting the growth of cartilage destroyed during wear and tear in osteoarthritis patients (Towheed, T. E., Arthritis and Rheumatism, 49, 601-604, 2003).
When taken orally as a dietary supplement in the form of glucosamine sulfate, it has been shown to exert protective effect against joint destruction and is selectively used by joint tissues to promote healthy joint function and show potential therapeutic effect in osteoarthritis (Perry, G. H., et al., Ann. Rheum. Dis., 31,440-448, 1972). Glucosamine has also been shown to address the root cause of osteoarthritis disease. It supports the body's natural ability to tackle the disease on its own by providing the building blocks to many structural components such as glucosaminoglycons to repair the damage caused by osteoarthritis.
N-acetylglucosamine, another bioavailable form of glucosamine, does not have any established negative side effects and is a valuable and important component of protein synthesis in the animal body that has a positive effect on tissue regeneration. N-acetylglucosamine has therapeutic potential in the prevention and/or treatment of a wide variety of diseases such as gastritis, food allergies, inflammatory bowel disease (IBD), diverticulitis, acute and chronic forms of rheumatoid arthritis and osteoarthritis, as well as the pathological conditions arising from metabolic disorders of the osteoarticular tissues.
Accordingly, it is well established that nutritional supplements containing glucosamine may be used as therapy for the treatment of connective tissues. U.S. Pat. No. 3,683,076 to Rovati et al. teaches that glucosamine sulfates are useful to treat arthritic conditions. U.S. Pat. No. 3,697,652 to Rovati et al. discloses that N-acetyl glucosamine can be used to treat degenerative afflictions of the joints. U.S. Pat. Nos. 5,364,845, 5,587,363 and 6,492,349 (to Henderson) show that glucosamine, chondroitin and manganese are used to protect and repair connective tissue. In U.S. Pat. No. 5,840,715 to Florio, N-acetyl glucosamine sulfate, chondroitin sulfate, gamma linolenic acid ercosapentaenoic acid and docosahexaneoic acid, and manganese aspartate are combined to treat arthritis symptoms. U.S. Pat. No. 5,916,565 to Rose et al. teaches a composition comprised of D-glucosamine hydrochloride, chondroitin sulfate, cayenne, ginger, turmeric, yucca, Devil's Claw, nettle leaf, Black Cohosh, alfalfa, and celery seeds to repair and maintain damaged tissues in joints of vertebrates. In U.S. Pat. No. 5,922,692, Marino discloses that glucosamine sulfate and chondroitin sulfate can be added to foodstuffs. Lexington, Ky.) for oral administration of hyaluronic acid.
Despite the health benefits associated with glucosamine, there exist several unfavorable properties of this compound as well. Glucosamine is highly hygroscopic and its amino group oxidizes readily. One approach to resolve the stability issues associated with glucosamine, more specifically glucosamine sulphate, is to protect the molecule from contact with oxygen in the form of coated tablets, ampules or capsules. Alternatively, anti-oxidants may be used, such as sodium hyposulphite, to block the oxidation of the amino group. However, neither approach addresses the problem of the hygroscopic nature of glucosamine. This necessitates the preparation of these forms in environments with a very low relative humidity. However, even this approach is less than desirable because the shelf life is practically insufficient for their use.
Additional approaches believed to improve the stability of glucosamine include U.S. Pat. No. 4,642,340 which describes formation of a crystalline mixed salt of glucosamine sulphate with an alkali halide, namely sodium chloride. Formation of a mixed salt increases the chemical stability at ambient temperature and renders the glucosamine sulphate less hygroscopic. EP-214642 describes an improved method for formation of a mixed salt of glucosamine sulphate with alkali halides. Specifically it describes preparation of a mixed salt with potassium chloride. The potassium salt has the advantage of avoiding the disfavorable adiuretic effect of sodium chloride, which is particularly detrimental in case of patients with cardio-vascular disease. The mixed salt is essentially stable over 30 days at 75% relative humidity/20° C. EP-444000 describes the stabilization of an oral dosage form of glucosamine sulphate by providing ascorbic acid as an anti-oxidant in an amount being of at least ¼ of that of glucosamine sulphate. Calcium carbonate is required as a desiccant. The formulation is suited for manufacturing oral dosage forms such as tablets, most preferably capsules.
Despite the fact that others have reported formulations and methods that are believed to improve the stability of glucosamine, it has been surprisingly found that the United States Pharmacopoeia (USP) methods do not separate the degradants of glucosamine from pure glucosamine. Yu Shao, in J. Pharm and Biomed Analysis, has published an analytical method that will separate the degradants of glucosamine from pure glucosamine. J Agric Food Chem, 51(21), p 6345 2003. This article identifies potential glucosamine degradants and chemical pathways of degradation. Such glucosamine degradants include 5-(hydroxymethyl)-2-furaldehyde (5-HMF), 2-(tetrahydroxybutyl)-5-(3′,4′-dihydroxy-1′-trans-butenyl)pyrazine, 2-(tetrahydroxybutyl)-5-(2′,3′,4′-trihydroxybutyl)pyrazine, commonly known as deoxyfructosazine and 2,5-bis(tetrahydroxybutyl)pyrazine (fructosazine).
Therefore, it is the inventors' belief that many products in the marketplace that may appear stable by the USP methods are in fact not stable. Testing of commercially available products confirmed that glucosamine degradation products were present. The degradants were especially observed in supplements containing glucosamine, vitamins and minerals. For example, the inventors tested the commercially available products Weil, ArthX-Plus and Joint Strength. Dr. Weil's glucosamine capsules state on the label that it contains glucosamine in an amount of 500 mg. Upon testing with the Yu Shao method however the product was found to contain 88% of the label claim amount of glucosamine. Additionally, the degradant fructosazine was present. Arth-X-Plus, which contains a combination of glucosamine sulphate, calcium hydroxyapatite, and a variety of other vitamins, minerals and other herbal supplements, was also tested utilizing the Yu Shao method and was found to contain glucosamine degradants fructosazine and deoxyfructosazine. Lastly, Joint Strength, which contains Vitamins C, D3, Vitamin K1, Riboflavin, Vitamin B-6, Calcium, Iodine, Magnesium, Zinc, Copper, Manganese, Molybdenum was tested utilizing the Yu Shao method and was found to contain both glucosamine degradant fructosazine and deoxyfructoxazine.
Therefore, many products in the marketplace that may appear stable by the USP methods are in fact not stable and contain degradants. Accordingly, despite prior efforts to stabilize glucosamine, the therapeutic importance of this compound necessitates the need to develop alternate methods of stabilizing glucosamine. The present invention provides a composition that includes glucosamine in a highly storage-stable form. Additionally, the present invention provides for a method of manufacture for highly storage-stable forms of glucosamine containing compositions that will improve the packaged product stability and retention of glucosamine.